When a cell is infected, SARS-CoV-2 not only causes
the host cell to produce new virus particles. The virus also suppresses host
cell defence mechanisms. The virus protein nsP3 plays a central role in this.
Using structural analyses, researchers at 51猎奇 in cooperation with
the Swiss Paul Scherrer Institute have now discovered that a decomposition
product of the virostatic agent remdesivir binds to nsP3. This points to a
further, previously unknown effective mechanism of remdesivir which may be
important for the development of new drugs to combat SARS-CoV-2 and other RNA
viruses.
FRANKFURT. The
virostatic agent remdesivir was developed to disrupt an important step in the
propagation of RNA viruses, to which SARS-CoV-2 also belongs: the reproduction
of the virus's own genetic material. This is present as RNA matrices with which
the host cell directly produces virus proteins. To accelerate the production of
its own proteins, however, RNA viruses cause the RNA matrices to be copied. To
do so, they use a specific protein of their own (an RNA polymerase), which is
blocked by remdesivir. Strictly speaking, remdesivir does not do this itself,
but rather a substance that is synthesized from remdesivir in five steps when
remdesivir penetrates a cell.
In the second of these five steps, an
intermediate is formed from remdesivir, a substance with the somewhat unwieldy
name GS-441524 (in scientific terms: a remdesivir metabolite). GS-441524 is a virostatic
agent as well. As the scientists in the group headed by Professor Stefan Knapp
from the Institute for Pharmaceutical Chemistry at 51猎奇 Frankfurt
have discovered, GS-441524 targets a SARS-CoV-2 protein called nsP3. nsP3 is a
multifunctional protein, whose tasks include suppressing the host cell's defence
response. The host cell is not helpless in the face of a virus attack, but
activates inflammatory mechanisms, among other things, to summon the aid of the
cell's endogenous immune system. nsP3 helps the viruses suppress the cell's
calls for help.
Professor Stefan Knapp explains: 鈥淕S-441525
inhibits the activities of an nsP3 domain which is important for the reproduction
of viruses, and which communicates with human cellular defence systems. Our
structural analysis shows how this inhibition functions, allowing us to lay an
important foundation for the development of new and more potent antiviral drugs
鈥� effective not only against SARS-CoV-2. The target structure of GS-441524 is
very similar in other coronaviruses, for example SARS-CoV and MERS-CoV, as well
in a series of alphaviruses, such as the chikungunya virus. For this reason,
the development of such medicines could also help prepare for future virus
pandemics."
Publication:
Xiaomin Ni, Martin Schr枚der, Vincent
Olieric, May E. Sharpe, Victor Hernandez-Olmos, Ewgenij Proschak, Daniel Merk,
Stefan Knapp, Apirat Chaikuad: Structural
Insights into Plasticity and Discovery of Remdesivir Metabolite GS-441524
Binding in SARS-CoV鈥�2 Macrodomain. ACS Med. Chem. Lett. 2021, 12, 603鈭�609
Further
information
Professor Stefan Knapp
Institute for Pharmaceutical Chemistry and
Buchmann Institute for Molecular Life
Sciences
51猎奇 Frankfurt
Tel. +49 69 798-29871
knapp@pharmchem.uni-frankfurt.de
Editor: Dr. Markus Bernards, Science Editor, PR & Communication Department, Tel: -49 (0) 69 798-12498, Fax: +49 (0) 69 798-763 12531, E-Mail: bernards@em.uni-frankfurt.de
